A combination of rituximab (Rituxan) and the PI3K-delta inhibitor idelalisib was associated with a >70% improvement in overall survival (OS) in patients with high-risk relapsed/refractory chronic lymphocytic leukemia (CLL).
Richard Furman, MD
According to phase III data from Study 116 presented at the 55th Annual Meeting of the American Society of Hematology, a combination of rituximab (Rituxan) and the PI3K-delta inhibitor idelalisib was associated with a >70% improvement in overall survival (OS) in patients with high-risk relapsed/refractory chronic lymphocytic leukemia (CLL).
The idelalisib combination also improved progression-free survival (PFS), the primary endpoint of the trial, by >80% compared with the comparator arm of rituximab plus placebo.
The two regimens had similar adverse-event (AE) profiles, according to lead author Richard Furman, MD, who reported the results at the meeting.
“In patients with heavily pretreated, relapsed CLL who are not suitable for cytotoxic chemotherapy and at high risk for poor outcome, idelalisib plus rituximab significantly improved progression-free survival, objective response rate, and overall survival,” said Furman, head of the CLL and Waldenstrom’s Macroglobulinemia Program at Weill Cornell Medical College. “Idelalisib and rituximab provided effective, durable disease control and improved overall survival for patients with advanced CLL, including high-risk patients.”
Idelalisib is highly a selective inhibitor of PI3K-delta, an isoform found primarily in leukocytes. The molecule has a central role in activation, proliferation, migration, and survival of B lymphocytes. The isoform induces hyperactivation in a variety of B-cell malignancies, said Furman.
Favorable results from early clinical trials led to the phase III, multicenter, multinational Study 116. Investigators in North America and Europe randomized 220 patients with relapsed/refractory CLL in a 1:1 ratio to receive rituximab plus either idelalisib (150 mg twice daily) or placebo. Treatment was scheduled to continue for 6 months.
At progression, patients could continue treatment in a single-agent extension study (117). Patients initially randomized to idelalisib received a higher dosage (300 mg twice daily) in the extension study, whereas patients randomized to placebo received the idelalisib dosage from the primary stage.
On average, patients had received three prior regimens and were considered ineligible for additional chemotherapy. Between 80% and 90% of the patients had a Cumulative Illness Rating Score >6; 40% to 45% had a 17p deletion or TP53 mutation; 80% to 85% had unmutatedIGHV; and about 40% of the patients had a creatinine clearance of <60 mL/min.
The trial was halted and crossover was allowed following a positive risk-benefit review from an independent data monitoring committee at an interim analysis.
When the trial stopped, the median PFS in the placebo group was 5.5 months, whereas the median had yet to be reached in the idelalisib arm. The difference in PFS translated into an 85% reduction in the hazard for the idelalisib group versus the placebo group (hazard ratio [HR] = 0.15; 95% CI, 0.08-0.28;P<.001). The 24-week PFS was 93% with idelalisib/rituximab and 46% for placebo/rituximab. The PFS benefit was consistent across all prespecified subgroups, including sex, age, and mutation status.
Analysis of OS yielded a hazard ratio of 0.28, representing a 72% reduction in the hazard for patients treated with idelalisib versus placebo (95% CI, 0.09-0.86;P= .018).
Objective response rate, a secondary endpoint, was six times higher with idelalisib versus placebo (81% vs 13%; odds ratio = 29.92;P<.0001).
Lymphadenopathy improved in all patients in the idelalisib arm, and 93% of the patients had at least a 50% improvement, the criterion for lymph node response. In contrast, 4% of placebo-treated patients had lymph node responses.
More than 90% of patients in each group had at least one AE. The most common AEs (all grades) in the idelalisib group were pyrexia (29%), fatigue (24%), nausea (24%), chills (22%), and diarrhea (19%). In the placebo arm, the most common AEs (all grades) were infusion-related reaction (28%), fatigue (27%), cough (25%), nausea (22%), and dyspnea (19%).
The incidence of grade ≥3 adverse events was 56.4% with idelalisib versus 47.7% with placebo. Serious adverse events occurred in 40% of the idelalisib group and 34.6% of the placebo group.
The discontinuation rate associated with adverse events was 8.2% in the idelalisib arm and 10.3% in the placebo group. Additionally, four deaths (3.6%) occurred in idelalisib group, as did 12 (11.2%) in the placebo group.
Furman RR, Sharman JP, Coutre SE, et al. A phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib and rituximab for previously treated patients with chronic lymphocytic leukemia (CLL). Presented at: 55th ASH Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract LBA-6.